tbuckley/cabot-search huggingface dataset:
Norepinephrine links astrocytic activity to regulation of cortical state
Authors: Michael E. Reitman, Vincent Tse, Xuelong Mi, Drew D. Willoughby, Alba Peinado, Alexander Aivazidis, Bat-Erdene Myagmar, Paul C. Simpson, Omer A. Bayraktar, Guoqiang Yu, Kira E. Poskanzer
Journal: Nature Neuroscience (2023)

Abstract Cortical state, defined by population-level neuronal activity patterns, determines sensory perception. While arousal-associated neuromodulators—including norepinephrine (NE)—reduce cortical synchrony, how the cortex resynchronizes remains unknown. Furthermore, general mechanisms regulating cortical synchrony in the wake state are poorly understood. Using in vivo imaging and electrophysiology in mouse visual cortex, we describe a critical role for cortical astrocytes in circuit resynchronization. We characterize astrocytes’ calcium responses to changes in behavioral arousal and NE, and show that astrocytes signal when arousal-driven neuronal activity is reduced and bi-hemispheric cortical synchrony is increased. Using in vivo pharmacology, we uncover a paradoxical, synchronizing response to Adra1a receptor stimulation. We reconcile these results by demonstrating that astrocyte-specific deletion of Adra1a enhances arousal-driven neuronal activity, while impairing arousal-related cortical synchrony. Our findings demonstrate that astrocytic NE signaling acts as a distinct neuromodulatory pathway, regulating cortical state and linking arousal-associated desynchrony to cortical circuit resynchronization.
The Niemann-Pick type diseases – A synopsis of inborn errors in sphingolipid and cholesterol metabolism
Authors: Frank W. Pfrieger
Journal: Progress in Lipid Research (2023)

Disturbances of lipid homeostasis in cells provoke human diseases. The elucidation of the underlying mechanisms and the development of efficient therapies represent formidable challenges for biomedical research. Exemplary cases are two rare, autosomal recessive, and ultimately fatal lysosomal diseases historically named "Niemann-Pick" honoring the physicians, whose pioneering observations led to their discovery. Acid sphingomyelinase deficiency (ASMD) and Niemann-Pick type C disease (NPCD) are caused by specific variants of the sphingomyelin phosphodiesterase 1 (SMPD1) and NPC intracellular cholesterol transporter 1 (NPC1) or NPC intracellular cholesterol transporter 2 (NPC2) genes that perturb homeostasis of two key membrane components, sphingomyelin and cholesterol, respectively. Patients with severe forms of these diseases present visceral and neurologic symptoms and succumb to premature death. This synopsis traces the tortuous discovery of the Niemann-Pick diseases, highlights important advances with respect to genetic culprits and cellular mechanisms, and exposes efforts to improve diagnosis and to explore new therapeutic approaches.
Prediction of Malignant Thyroid Nodules Using 18F-FDG PET/CT–Based Radiomics Features in Thyroid Incidentalomas
Authors: Woo Seog Ko, Seong-Jang Kim
Journal: Clinical Nuclear Medicine (2023)

Objective The purpose of the current study was to evaluate the diagnostic performances of 18 F-FDG PET/CT–based radiomics features for prediction of malignant thyroid nodules (TNs) in thyroid incidentaloma (TI). Methods PubMed, Cochrane database, and EMBASE database, from the earliest available date of indexing through December 31, 2022, were searched for studies evaluating diagnostic performance of 18 F-FDG PET/CT–based radiomics features for prediction of malignant TNs in TI. We determined the sensitivities and specificities across studies, calculated positive and negative likelihood ratios (LRs; positive and negative LRs), and estimated pooled area under the curve. Results Across 5 studies (518 patients), the pooled sensitivity of 18 F-FDG PET/CT was 0.77 (95% confidence interval [CI], 0.67–0.84), and a pooled specificity was 0.67. Likelihood ratio syntheses gave an overall positive LR of 2.3 (95% CI, 1.5–3.6) and negative LR of 0.35 (95% CI, 0.26–0.47). The pooled diagnostic odds ratio was 7 (95% CI, 4–12). The pooled area under the curve of fixed effects was 0.763 (95% CI, 0.736–0.791), and that of random effects was 0.763 (95% CI, 0.721–0.805). Conclusion 18 F-FDG PET/CT–based radiomics features showed a good diagnostic performance for prediction of malignant TNs in TI.
Characterization of multi-DAA resistance using a novel hepatitis C virus genotype 3a infectious culture system
Authors: Carlota Fernandez-Antunez, Kuan Wang, Ulrik Fahnøe, Lotte S. Mikkelsen, Judith M. Gottwein, Jens Bukh, Santseharay Ramirez
Journal: Hepatology (2023)

Background and Aims: The high HCV infection cure rates achieved with direct-acting antiviral (DAA) treatments could be compromised in the future by the emergence of antiviral resistance. Thus, it is essential to understand the viral determinants that influence DAA resistance, which is most prevalent in genotype 3. We aimed at studying how resistance to protease-, NS5A-, and NS5B-inhibitors influences the activities of glecaprevir/pibrentasvir, sofosbuvir/velpatasvir, and sofosbuvir/velpatasvir/voxilaprevir in cell culture, and how the HCV genome adapts to selective pressure by successive rounds of treatment failure. Approach and Results: A previously developed in vivo infectious cDNA clone of strain S52 (genotype 3a) was adapted to efficiently replicate and propagate in human hepatoma cells (Huh7.5) using 31 adaptive substitutions. DAA escape experiments resulted in the selection of S52 variants with decreased drug susceptibility (resistance), which was linked to the emergence of known resistance-associated substitutions (RASs). NS5A-inhibitor resistance was sufficient to promote treatment failure with double-DAA but not triple-DAA regimens. Enhanced viral fitness associated with the selection of sofosbuvir resistance accelerated escape from DAAs. After serial DAA treatment failure, HCV genetic evolution led to a complex genome-wide network of substitutions, some of which coevolved with known RASs. Conclusions: Baseline NS5A-RAS can compromise the efficacy of double-DAA pangenotypic regimens for HCV genotype 3, and enhanced viral fitness can accelerate treatment failure. Persistence of RASs after successive treatment failure is facilitated by the remarkable evolutionary capacity and plasticity of the HCV genome. Proof-of-concept for the potential development of multi-DAA resistance is shown.
Changing trends, clinicopathological characteristics, surgical treatment patterns, and prognosis of schistosomiasis-associated versus non-schistosomiasis-associated colorectal cancer: a large retrospective cohort study of 31 153 cases in Shanghai, China (2001–2021)
Authors: Nanxin Zheng, Hao Wang, Qing Yu, Chen Wang, Chen Guang Bai, An Fu Pan, Jianjun Jiang, Jian Lu, Si Min Dai, Zubing Mei, Wei Zhang, Xian Hua Gao
Journal: International Journal of Surgery (2023)

Background: With the elimination of schistosomiasis in China, its role in the pathogenesis of colorectal cancer (CRC) has decreased. However, the trends, clinicopathological features, surgical treatment patterns, and prognosis of schistosomiasis-associated CRC (SACRC) versus non-schistosomiasis-associated CRC (NSACRC) in China remain unclear. Materials and methods: The percentage trend of SACRC in CRC patients in China was analyzed using data retrieved from the Pathology Registry of Changhai Hospital (2001–2021). Clinicopathological characteristics, surgical treatment patterns, and prognosis-related parameters were compared between the two groups. Multivariate Cox regression analyses were performed for disease-free survival (DFS) and overall survival (OS). Results: A total of 31 153 CRC cases were included, with 823 (2.6%) cases of SACRC and 30 330 (97.4%) cases of NSACRC. The average percentage of SACRC cases has decreased continuously from 3.8 to 1.7% (from 2001 to 2021). Compared with the NSACRC group, the SACRC group had more men, older age at diagnosis, lower BMI, fewer symptoms; higher rates of rectal cancer, comorbidities, KRAS mutation, multiple primary CRC and concomitant polyps; less lymph node metastasis, distant metastasis, vascular invasion, and tumor budding; less preoperative radiotherapy and preoperative chemotherapy; and more positive resection margins and postoperative targeted therapy. There were no significant differences between the two groups regarding laparoscopic surgery, palliative resection, extended radical resection, or ostomy. Moreover, the SACRC group had adverse DFS and similar OS compared with the NSACRC group. In multivariate analyses, schistosomiasis was not an independent predictor of DFS or OS. Conclusion: The percentage of SACRC in CRC (2.6%) in our hospital was very low, and it decreased continuously over the last two decades, indicating that schistosomiasis is no longer an important risk factor for CRC in Shanghai, China. Patients with SACRC have distinct clinicopathological, molecular, and treatment-related features and survival rates similar to those with NSACRC.
Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results
Authors: Isabella C. Glitza Oliva, Sherise D. Ferguson, Roland Bassett, Alexandra P. Foster, Ida John, Tarin D. Hennegan, Michelle Rohlfs, Jessie Richard, Masood Iqbal, Tina Dett, Carol Lacey, Natalie Jackson, Theresa Rodgers, Suzanne Phillips, Sheila Duncan, Lauren Haydu, Ruitao Lin, Rodabe N. Amaria, Michael K. Wong, Adi Diab, Cassian Yee, Sapna P. Patel, Jennifer L. McQuade, Grant M. Fischer, Ian E. McCutcheon, Barbara J. O’Brien, Sudhakar Tummala, Matthew Debnam, Nandita Guha-Thakurta, Jennifer A. Wargo, Fernando C. L. Carapeto, Courtney W. Hudgens, Jason T. Huse, Michael T. Tetzlaff, Elizabeth M. Burton, Hussein A. Tawbi, Michael A. Davies
Journal: Nature Medicine (2023)

Abstract There is a critical need for effective treatments for leptomeningeal disease (LMD). Here, we report the interim analysis results of an ongoing single-arm, first-in-human phase 1/1b study of concurrent intrathecal (IT) and intravenous (IV) nivolumab in patients with melanoma and LMD. The primary endpoints are determination of safety and the recommended IT nivolumab dose. The secondary endpoint is overall survival (OS). Patients are treated with IT nivolumab alone in cycle 1 and IV nivolumab is included in subsequent cycles. We treated 25 patients with metastatic melanoma using 5, 10, 20 and 50 mg of IT nivolumab. There were no dose-limiting toxicities at any dose level. The recommended IT dose of nivolumab is 50 mg (with IV nivolumab 240 mg) every 2 weeks. Median OS was 4.9 months, with 44% and 26% OS rates at 26 and 52 weeks, respectively. These initial results suggest that concurrent IT and IV nivolumab is safe and feasible with potential efficacy in patients with melanoma LMD, including in patients who had previously received anti-PD1 therapy. Accrual to the study continues, including in patients with lung cancer. ClinicalTrials.gov registration: NCT03025256 .
TREM2 acts as a receptor for IL-34 to suppress acute myeloid leukemia in mice
Authors: Xiaoling Xie, Wuju Zhang, Min Xiao, Tiantian Wei, Yingqi Qiu, Jingyang Qiu, Hao Wang, Zeyou Qiu, Sheng Zhang, Yating Pan, Linlin Mao, Yuhua Li, Bin Guo, Wanwen Yang, Yuxing Hu, Shujie Hu, Yan Gong, Jun Yang, Guozhi Xiao, Yue Zhang, Xiaochun Bai
Journal: Blood (2023)

The bone marrow microenvironment supports leukocyte mobilization and differentiation and controls the development of leukemias, including acute myeloid leukemia (AML). Here, we found that the development of AML xenotransplants was suppressed in mice with osteoclasts Tsc1 deletion. Tsc1-deficient osteoclasts released a high level of IL-34, which efficiently induced AML cell differentiation and prevented AML progression in various preclinical models. Conversely, AML development was accelerated in IL-34-deficient mice. Interestingly, IL-34 inhibited AML independent of its known receptors, but bound directly to triggering receptor expressed on myeloid cells 2 (TREM2), a key hub of immune signals. TREM2-deficient AML cells and normal myeloid cells were resistant to IL-34 treatment. Mechanistically, IL-34-TREM2 binding rapidly phosphorylated Rasal3 and inactivated ERK1/2 signaling to prevent AML cell proliferation and stimulate differentiation. Furthermore, TREM2 was downregulated in AML patients and associated with a poor prognosis. This study identified TREM2 as a novel receptor for IL-34, indicating a promising strategy for overcoming AML differentiation blockade in AML patients.
Development and validation of a preoperative nomogram for predicting the surgical difficulty of laparoscopic colectomy for right colon cancer: a retrospective analysis
Authors: Ao Yu, Yuekai Li, Haifeng Zhang, Guanbo Hu, Yuetang Zhao, Jinghao Guo, Meng Wei, Wenbin Yu, Zhibo Yan
Journal: International Journal of Surgery (2023)

In laparoscopic right hemicolectomy for right colon cancer, complete mesocolic excision is a standard procedure that involves extended lymphadenectomy and blood vessel ligation. This study aimed to establish a nomogram to facilitate evaluation of the surgical difficulty of laparoscopic right hemicolectomy based on preoperative parameters.The preoperative clinical and computed tomography-related parameters, operative details, and postoperative outcomes were analyzed. The difficulty of laparoscopic colectomy was defined using the scoring grade reported by Escal et al . with modifications. Multivariable logistic analysis was performed to identify parameters that increased the surgical difficulty. A preoperative nomogram to predict the surgical difficulty was established and validated.A total of 418 consecutive patients with right colon cancer who underwent laparoscopic radical resection at a single tertiary medical center between January 2016 and May 2022 were retrospectively enrolled. The patients were randomly assigned to a training data set ( n =300, 71.8%) and an internal validation data set ( n =118, 28.2%). Meanwhile, an external validation data set with 150 consecutive eligible patients from another tertiary medical center was collected. In the training data set, 222 patients (74.0%) comprised the non-difficulty group and 78 (26.0%) comprised the difficulty group. Multivariable analysis demonstrated that adipose thickness at the ileocolic vessel drainage area, adipose area at the ileocolic vessel drainage area, adipose density at the ileocolic vessel drainage area, presence of the right colonic artery, presence of type III Henle's trunk, intra-abdominal adipose area, plasma triglyceride concentration, and tumor diameter at least 5 cm were independent risk factors for surgical difficulty; these factors were included in the nomogram. The nomogram incorporating seven independent predictors showed a high C-index of 0.922 and considerable reliability, accuracy, and net clinical benefit.The study established and validated a reliable nomogram for predicting the surgical difficulty of laparoscopic colectomy for right colon cancer. The nomogram may assist surgeons in preoperatively evaluating risk and selecting appropriate patients.
The implications of salivary exosomes as a theranostic secret of human cancers with a focus on oral cancer
Authors: Wei Liu, Jinbing Wang, Xuemin Shen, Huan Shi
Journal: International Journal of Surgery (2023)

aDepartment of Oral Mucosal Diseases, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China bCollege of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China cDepartment of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China dDepartment of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online ■ ■ *Corresponding Author. Address: Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai 200011, China. Tel.: +86 21 23271699; fax: +86 21 63087037. E-mail address: [email protected] (J. Wang). *Corresponding Author. Address: Department of Oral Mucosal Diseases, Shanghai Ninth People's Hospital, Shanghai 200011, China. Tel.: +86 21 63162851; fax: +86 21 63087076. E-mail address: [email protected] (X. Shen). *Corresponding Author. Address: Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai 200011, China. Tel.: +86 21 23271699; fax: +86 21 63087052. E-mail address: [email protected] (H. Shi). This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0/
Intraoperative dexmedetomidine on postoperative pain in gastrointestinal surgery: an observational study
Authors: Xuecai Lv, Haoyun Zhang, Jie Gao, Aisheng Hou, Yulong Ma, Zhikang Zhou, Weidong Mi, Hong Zhang, Yanhong Liu
Journal: International Journal of Surgery (2023)

Dexmedetomidine (DEX) is widely used for adjuvant sedation and analgesia in gastrointestinal surgeries. The authors aimed to reassess the effects of intraoperative DEX on acute pain by comprehensive analysis of the multiple dimensions of pain.In this multicentre cohort study, patients undergoing gastrointestinal surgeries were prospectively enrolled in the China Acute Postoperative Pain Study. Patients were divided into DEX and non-DEX groups based on whether DEX was used during surgery. Patient satisfaction with pain treatment (rated on a numeric rating score, 0-10) and other pain-related outcomes were evaluated using the International Pain Outcome Questionnaire on the first postoperative day. The effects of intraoperative DEX were analyzed using logistic or linear regression for dichotomous or continuous variables, respectively. Propensity score matching and subgroup analyses were performed to appraise the correlation between intraoperative DEX and postoperative pain outcomes.Of the 1260 patients eligible for analysis, 711 (56.4%) received intraoperative DEX. Propensity score matching resulted in 415 patients in each group. Intraoperative DEX was associated with higher patient satisfaction (β: 0.556; 95% CI: 0.366-0.745), and a decrease in the percentage of time spent in severe pain (β: -0.081; 95% CI: -0.104- -0.058), anxiety (odds ratio: 0.394; 95% CI: 0.307-0.506), helplessness (odds ratio: 0.539; 95% CI: 0.411-0.707), and postoperative opioid consumption (β: -16.342; 95% CI: -27.528- -5.155).Intraoperative DEX was associated with the prognosis of acute postoperative pain in multiple aspects in patients undergoing major gastrointestinal surgery, including increased patient satisfaction, and a reduction in the duration of severe pain, postoperative anxiety and helplessness, and postoperative opioid consumption. Future studies to determine the dose and timing of DEX administration on pain-related outcomes are warranted.
Risk factors for achieving textbook outcome after laparoscopic duodenum-preserving total pancreatic head resection: a retrospective cohort study
Authors: Yi Wu, Nuerabula Wujimaimaiti, Jingxiong Yuan, Shizhen Li, Hang Zhang, Min Wang, Renyi Qin
Journal: International Journal of Surgery (2023)

Introduction: The risk factors for achieving textbook outcome (TO) after laparoscopic duodenum-preserving total pancreatic head resection (LDPPHR-t) are unknown, and no relevant articles have been reported so far. The aim of this study was to identify the risk factors for achieving TO after LDPPHR-t. Methods: The risk factors for achieving TO after LDPPHR-t were retrospectively evaluated by logistic regression analysis in 31 consecutive patients from May 2020 to December 2021. Results: All LDPPHR-t procedures were successfully performed without conversion. There was no death within 90 days after surgery and no readmission within 30 days after discharge. The percentage of achieving TO after LDPPHR-t was 61.3% (19/31). Among the six TO items, the postoperative complication of grade B/C postoperative pancreatic fistula (POPF) occurred most frequently with 22.6%, followed by grade B/C bile leakage with 19.4%, Clavien–Dindo≥III complications with 19.4%, and grade B/C postpancreatectomy hemorrhage with 16.1%. POPF was the major obstacle to achieve TO after LDPPHR-t. Placing an endoscopic nasobiliary drainage (ENBD) catheter and prolonged operation time (&gt;311 min) were significantly associated with the decreased probability of achieving TO after LDPPHR-t (odd ratio (OR), 25.775; P =0.012 and OR, 16.378; P =0.020, respectively). Placing an ENBD catheter was the only significant independent risk factor for POPF after LDPPHR-t (OR, 19.580; P =0.017). Bile leakage was the independent risk factor for postpancreatectomy hemorrhage after LDPPHR-t (OR, 15.754; P =0.040). The prolonged operation time was significantly correlated with Clavien–Dindo grade≥III complications after LDPPHR-t (OR, 19.126; P =0.024). Conclusion: Placing the ENBD catheter was the independent risk factor for POPF and achieving TO after LDPPHR-t. In order to reduce POPF and increase the probability of achieving TO, placing an ENBD catheter should be avoided prior to LDPPHR-t.
Prediction of conditional survival in esophageal cancer in a population-based cohort study
Authors: Shao-Hua Xie, Giola Santoni, Matteo Bottai, Eivind Gottlieb-Vedi, Pernilla Lagergren, Jesper Lagergren
Journal: International Journal of Surgery (2023)

The authors aimed to produce a prediction model for survival at any given date after surgery for esophageal cancer (conditional survival), which has not been done previously.Using joint density functions, the authors developed and validated a prediction model for all-cause and disease-specific mortality after surgery with esophagectomy, for esophageal cancer, conditional on postsurgery survival time. The model performance was assessed by the area under the receiver operating characteristic curve (AUC) and risk calibration, with internal cross-validation. The derivation cohort was a nationwide Swedish population-based cohort of 1027 patients treated in 1987-2010, with follow-up throughout 2016. This validation cohort was another Swedish population-based cohort of 558 patients treated in 2011-2013, with follow-up throughout 2018.The model predictors were age, sex, education, tumor histology, chemo(radio)therapy, tumor stage, resection margin status, and reoperation. The medians of AUC after internal cross-validation in the derivation cohort were 0.74 (95% CI: 0.69-0.78) for 3-year all-cause mortality, 0.76 (95% CI: 0.72-0.79) for 5-year all-cause mortality, 0.74 (95% CI: 0.70-0.78) for 3-year disease-specific mortality, and 0.75 (95% CI: 0.72-0.79) for 5-year disease-specific mortality. The corresponding AUC values in the validation cohort ranged from 0.71 to 0.73. The model showed good agreement between observed and predicted risks. Complete results for conditional survival any given date between 1 and 5 years of surgery are available from an interactive web-tool: https://sites.google.com/view/pcsec/home .This novel prediction model provided accurate estimates of conditional survival any time after esophageal cancer surgery. The web-tool may help guide postoperative treatment and follow-up.